This is an application for a K23 award for Dr. Eric Judd, a nephrologist at the University of Alabama at Birmingham. Dr. Judd proposes a novel treatment pathway for chronic kidney disease (CKD), and his long-term career goal is to become an independent clinical investigator devoted to identifying and/or developing CKD-specific therapies. This award will allow Dr. Judd the resources and protected time to achieve the following career development goals: (1) to become an expert in endothelial and vascular function in CKD; (2) to implement advanced biostatistical methods in clinical trials (3) to become an independent, translational clinical investigator in the fields of vasculature and CKD. To achieve these goals, Dr. Judd has assembled a mentoring team comprised of a primary mentor, Dr. David Calhoun (an expert in vascular function testing including ultrasound assessment of flow-mediated dilation (FMD) and aldosterone physiology), a co-mentor, Dr. Michael Allon (an expert in clinical trials and vascular access in the late stages of CKD), and 3 content experts: Dr. Anupam Agarwal, PI for the NIDDK funded O'Brien Center at our institution; Dr. Rakesh Patel, an authority in measuring oxidative stress as a marker of endothelial function; and Dr. Gary Cutter, an expert in the statistical methods in clinical trials. Vascular endothelial dysfunction increases cardiovascular (CV) risk and contributes to the progression of CKD. Mineralocorticoid receptor (MR) antagonists have been shown to improve endothelial function, as well as decrease CV mortality and proteinuria. The specific biochemical pathways that produce these pharmacological effects for MR antagonists, however, are poorly understood. Dr. Judd will investigate the effect of MR antagonism on endothelial function in patients with moderate (stage III) CKD by performing a randomized, controlled trial. Three specific aims are proposed: Aim 1: To determine if spironolactone improves endothelial function as compared to amiloride in patients with stage III CKD; Aim 2: To determine if oxidative stress is associated with changes in endothelial function by spironolactone compared to amiloride in patients with stage III CKD; and Aim 3: To determine if endothelial dysfunction contributes to albuminuria in patients with stage III CKD. Relevance: A better understanding of the mechanisms of kidney function decline in CKD could lead to important interventions and prevention strategies, translating into alleviating patient suffering, caregiver burden, and health care costs.